The first step of HIV infection is binding of HIV to its target cells. Study of HIV binding has led to an understanding of HIV pathogenesis and development of preventive and therapeutic drugs. It is known that binding of HIV to target cells is mediated by the HIV envelope protein, gp160. Therefore, the interaction of gp160 with its receptors, including CD4, chemokine receptors, and C-type lentins, has been intensively studied. However, the number of gp160 molecules expressed on the HIV envelope is low (14 trimers of pg160/virion), indicating that there is a mechanism mediating HIV binding through an envelope protein-independent mechanism. In fact, one research group found that amyloid fibrils in semen dramatically enhance HIV replication. We also found that a factor in serum can mediate binding of pseudotyped HIV vectors in an envelope-protein independent manner. The factor bridges viral vectors to cells and increases viral transduction 3- to 30-fold. This pathway is typically used for removal of dead cells by phagocytes. We have found that HIV vectors use apoptotic mimicry to enter into target cells. In the proposed studies, we will investigate whether this novel mechanism of viral binding is involved in HIV binding and replication. Elucidation of this mechanism will open new avenues for understanding HIV pathogenesis and replication, which will facilitate development of novel preventive and therapeutic approaches. PUBLIC HEALTH RELEVANCE: Although many anti-HIV drugs have been developed, elimination of HIV from infected patients with current approaches is still very difficult, using anti-viral drugs targeting intracellular events of HIV replication, including reverse transcription, processing of viral proteins, integration, and antibodies against viral envelope proteins. In this proposal, we will study a novel mechanism of HIV binding to target cells, which is mediated in an envelope protein-independent manner. Identification of this novel binding mechanism will lead to new approaches to prevent HIV transmission among people and to inhibit HIV replication in patients.